The objective of this research is to investigate the factors that determine hormone responsiveness in metastatic human breast cancers and the mechanisms by which this is lost during therapy. We propose to investigate the following closely related problems: the identity of the functional cell-hormone effector unit in estrogen-induced proliferation of estrogen-dependent metastatic cells; the kinetic variables in estrogen-dependent growth, and their application to an effective chemotherapy; hormonal eradication of dormant estrogen-dependent metastatic cells; the conversion of hormone-dependent cell to unresponsive cells, and the role played by adjuvant therapies in that transition; and finally, the role of hormones in selection of hormone-responsive metastatic stem cells from primary tumors. A direct approach to these problems has been made possible by a new experimental structure which combines, in sequence, the in vitro cloning of hormone-dependent malignant cells from human breast metastases, the growth of cloned cells in athymic mice, and recloning of tumor cells in vitro.